Impact of Tissue Damage and Hemodynamics on Restenosis Following Percutaneous Transluminal Angioplasty: A Patient-Specific Multiscale Model.

Multiscale agent-based modeling frameworks have recently emerged as promising mechanobiological models to capture the interplay between biomechanical forces, cellular behavior, and molecular pathways underlying restenosis following percutaneous transluminal angioplasty (PTA). However, their applications are mainly limited to idealized scenarios. Herein, a multiscale agent-based modeling framework for investigating restenosis following PTA in a patient-specific superficial femoral artery (SFA) is proposed. The framework replicates the 2-month arterial wall remodeling in response to the PTA-induced injury and altered hemodynamics, by combining three modules: (i) the PTA module, consisting in a finite element structural mechanics simulation of PTA, featuring anisotropic hyperelastic material models coupled with a damage formulation for fibrous soft tissue and the element deletion strategy, providing the arterial wall damage and post-intervention configuration, (ii) the hemodynamics module, quantifying the post-intervention hemodynamics through computational fluid dynamics simulations, and (iii) the tissue remodeling module, based on an agent-based model of cellular dynamics. Two scenarios were explored, considering balloon expansion diameters of 5.2 and 6.2 mm. The framework captured PTA-induced arterial tissue lacerations and the post-PTA arterial wall remodeling. This remodeling process involved rapid cellular migration to the PTA-damaged regions, exacerbated cell proliferation and extracellular matrix production, resulting in lumen area reduction up to 1-month follow-up. After this initial reduction, the growth stabilized, due to the resolution of the inflammatory state and changes in hemodynamics. The similarity of the obtained results to clinical observations in treated SFAs suggests the potential of the framework for capturing patient-specific mechanobiological events occurring after PTA intervention.

Modelling lower-limb peripheral arterial disease using clinically available datasets: impact of inflow boundary conditions on hemodynamic indices for restenosis prediction.

BACKGROUND AND OBJECTIVES: The integration of hemodynamic markers as risk factors in restenosis prediction models for lower-limb peripheral arteries is hindered by fragmented clinical datasets. Computed tomography (CT) scans enable vessel geometry reconstruction and can be obtained at different times than the Doppler ultrasound (DUS) images, which provide information on blood flow velocity. Computational fluid dynamics (CFD) simulations allow the computation of near-wall hemodynamic indices, whose accuracy depends on the prescribed inlet boundary condition (BC), derived from the DUS images. This study aims to: (i) investigate the impact of different DUS-derived velocity waveforms on CFD results; (ii) test whether the same vessel areas, subjected to altered hemodynamics, can be detected independently of the applied inlet BC; (iii) suggest suitable DUS images to obtain reliable CFD results. METHODS: CFD simulations were conducted on three patients treated with bypass surgery, using patient-specific DUS-derived inlet BCs recorded at either the same or different time points than the CT scan. The impact of the chosen inflow condition on bypass hemodynamics was assessed in terms of wall shear stress (WSS)-derived quantities. Patient-specific critical thresholds for the hemodynamic indices were applied to identify critical luminal areas and compare the results with a reference obtained with a DUS image acquired in close temporal proximity to the CT scan. RESULTS: The main findings indicate that: (i) DUS-derived inlet velocity waveforms acquired at different time points than the CT scan led to statistically significantly different CFD results (p<0.001); (ii) the same luminal surface areas, exposed to low time-averaged WSS, could be identified independently of the applied inlet BCs; (iii) similar outcomes were observed for the other hemodynamic indices if the prescribed inlet velocity waveform had the same shape and comparable systolic acceleration time to the one recorded in close temporal proximity to the CT scan. CONCLUSIONS: Despite a lack of standardised data collection for diseased lower-limb peripheral arteries, an accurate estimation of luminal areas subjected to altered near-wall hemodynamics is possible independently of the applied inlet BC. This holds if the applied inlet waveform shares some characteristics - derivable from the DUS report - as one matching the acquisition time of the CT scan.

Impact of endothelial shear stress on coronary atherosclerotic plaque progression and composition: A meta-analysis and systematic review.

BACKGROUND AND AIMS: Intracoronary pressure gradients and translesional flow patterns have been correlated with coronary plaque progression and lesion destabilization. In this study, we aimed to determine the relationship between endothelial shear stress and plaque progression and to evaluate the effect of shear forces on coronary plaque features. METHODS: A systematic review was conducted in medical on-line databases. Selected were studies including human participants who underwent coronary anatomy assessment with computational fluid dynamics (CFD)-based wall shear stress (WSS) calculation at baseline with anatomical evaluation at follow-up. A total of six studies were included for data extraction and analysis. RESULTS: The meta-analysis encompassed 31'385 arterial segments from 136 patients. Lower translesional WSS values were significantly associated with a reduction in lumen area (mean difference -0.88, 95% CI -1.13 to -0.62), an increase in plaque burden (mean difference 4.32, 95% CI 1.65 to 6.99), and an increase in necrotic core area (mean difference 0.02, 95% CI 0.02 to 0.03) at follow-up imaging. Elevated WSS values were associated with an increase in lumen area (mean difference 0.78, 95% CI 0.34 to 1.21) and a reduction in both fibrofatty (mean difference -0.02, 95% CI -0.03 to -0.01) and fibrous plaque areas (mean difference -0.03, 95% CI -0.03 to -0.03). CONCLUSION: This meta-analysis shows that WSS parameters were related to vulnerable plaque features at follow-up. These results emphasize the impact of endothelial shear forces on coronary plaque growth and composition. Future studies are warranted to evaluate the role of WSS in guiding clinical decision-making.

Smartphone-based particle tracking velocimetry for the in vitro assessment of coronary flows.

The present study adopts a smartphone-based approach for the experimental characterization of coronary flows. Technically, Particle Tracking Velocimetry (PTV) measurements were performed using a smartphone camera and a low-power continuous wave laser in realistic healthy and stenosed phantoms of left anterior descending artery with inflow Reynolds numbers approximately ranging from 20 to 200. A Lagrangian-Eulerian mapping was performed to convert Lagrangian PTV velocity data to a Eulerian grid. Eulerian velocity and vorticity data obtained from smartphone-based PTV measurements were compared with Particle Image Velocimetry (PIV) measurements performed with a smartphone-based setup and with a conventional setup based on a high-power double-pulsed laser and a CMOS camera. Smartphone-based PTV and PIV velocity flow fields substantially agreed with conventional PIV measurements, with the former characterized by lower average percentage differences than the latter. Discrepancies emerged at high flow regimes, especially at the stenosis throat, due to particle image blur generated by smartphone camera shutter speed and image acquisition frequency. In conclusion, the present findings demonstrate the feasibility of PTV measurements using a smartphone camera and a low-power light source for the in vitro characterization of cardiovascular flows for research, industrial and educational purposes, with advantages in terms of costs, safety and usability.

Association Between Automated 3D Measurement of Coronary Luminal Narrowing and Risk of Future Myocardial Infarction.

This study focuses on identifying anatomical markers with predictive capacity for long-term myocardial infarction (MI) in focal coronary artery disease (CAD). Eighty future culprit lesions (FCL) and 108 non-culprit lesions (NCL) from 80 patients underwent 3D quantitative coronary angiography. The minimum lumen area (MLA), minimum lumen ratio (MLR), and vessel fractional flow reserve (vFFR) were evaluated. MLR was defined as the ratio between MLA and the cross-sectional area at the proximal lesion edge, with lower values indicating more abrupt luminal narrowing. Significant differences were observed between FCL and NCL in MLR (0.41 vs. 0.53, p < 0.001). MLR correlated inversely with translesional vFFR (r = - 0.26, p = 0.0004) and was the strongest predictor of MI at 5 years (AUC = 0.75). Lesions with MLR < 0.40 had a fourfold increased MI incidence at 5 years. MLR is a robust predictor of future adverse coronary events.

Predicting Lipid-Rich Plaque Progression in Coronary Arteries Using Multimodal Imaging and Wall Shear Stress Signatures.

BACKGROUND: Plaque composition and wall shear stress (WSS) magnitude act as well-established players in coronary plaque progression. However, WSS magnitude per se does not completely capture the mechanical stimulus to which the endothelium is subjected, since endothelial cells experience changes in the WSS spatiotemporal configuration on the luminal surface. This study explores WSS profile and lipid content signatures of plaque progression to identify novel biomarkers of coronary atherosclerosis. METHODS: Thirty-seven patients with acute coronary syndrome underwent coronary computed tomography angiography, near-infrared spectroscopy intravascular ultrasound, and optical coherence tomography of at least 1 nonculprit vessel at baseline and 1-year follow-up. Baseline coronary artery geometries were reconstructed from intravascular ultrasound and coronary computed tomography angiography and combined with flow information to perform computational fluid dynamics simulations to assess the time-averaged WSS magnitude (TAWSS) and the variability in the contraction/expansion action exerted by WSS on the endothelium, quantifiable in terms of topological shear variation index (TSVI). Plaque progression was measured as intravascular ultrasound-derived percentage plaque atheroma volume change at 1-year follow-up. Plaque composition information was extracted from near-infrared spectroscopy and optical coherence tomography. RESULTS: Exposure to high TSVI and low TAWSS was associated with higher plaque progression (4.00±0.69% and 3.60±0.62%, respectively). Plaque composition acted synergistically with TSVI or TAWSS, resulting in the highest plaque progression (≥5.90%) at locations where lipid-rich plaque is exposed to high TSVI or low TAWSS. CONCLUSIONS: Luminal exposure to high TSVI, solely or combined with a lipid-rich plaque phenotype, is associated with enhanced plaque progression at 1-year follow-up. Where plaque progression occurred, low TAWSS was also observed. These findings suggest TSVI, in addition to low TAWSS, as a potential biomechanical predictor for plaque progression, showing promise for clinical translation to improve patient prognosis.

Blood Flow Energy Identifies Coronary Lesions Culprit of Future Myocardial Infarction.

The present study establishes a link between blood flow energy transformations in coronary atherosclerotic lesions and clinical outcomes. The predictive capacity for future myocardial infarction (MI) was compared with that of established quantitative coronary angiography (QCA)-derived predictors. Angiography-based computational fluid dynamics (CFD) simulations were performed on 80 human coronary lesions culprit of MI within 5 years and 108 non-culprit lesions for future MI. Blood flow energy transformations were assessed in the converging flow segment of the lesion as ratios of kinetic and rotational energy values (KER and RER, respectively) at the QCA-identified minimum lumen area and proximal lesion sections. The anatomical and functional lesion severity were evaluated with QCA to derive percentage area stenosis (%AS), vessel fractional flow reserve (vFFR), and translesional vFFR (ΔvFFR). Wall shear stress profiles were investigated in terms of topological shear variation index (TSVI). KER and RER predicted MI at 5 years (AUC = 0.73, 95% CI 0.65-0.80, and AUC = 0.76, 95% CI 0.70-0.83, respectively; p < 0.0001 for both). The predictive capacity for future MI of KER and RER was significantly stronger than vFFR (p = 0.0391 and p = 0.0045, respectively). RER predictive capacity was significantly stronger than %AS and ΔvFFR (p = 0.0041 and p = 0.0059, respectively). The predictive capacity for future MI of KER and RER did not differ significantly from TSVI. Blood flow kinetic and rotational energy transformations were significant predictors for MI at 5 years (p < 0.0001). The findings of this study support the hypothesis of a biomechanical contribution to the process of plaque destabilization/rupture leading to MI.

Determining the Mechanical Properties of Super-Elastic Nitinol Bone Staples Through an Integrated Experimental and Computational Calibration Approach.

Super-elastic bone staples have emerged as a safe and effective alternative for internal fixation. Nevertheless, several biomechanical aspects of super-elastic staples are still unclear and require further exploration. Within this context, this study presents a combined experimental and computational approach to investigate the mechanical characteristics of super-elastic staples. Two commercially available staples with distinct geometry, characterized by two and four legs, respectively, were examined. Experimental four-point bending tests were conducted to evaluate staple performance in terms of generated forces. Subsequently, a finite element-based calibration procedure was developed to capture the unique super-elastic behavior of the staple materials. Finally, a virtual bench testing framework was implemented to separate the effect of geometry from that of the material characteristics on the mechanical properties of the devices, including generated force, strain distribution, and fatigue behavior. The experimental tests indicated differences in the force vs. displacement curves between staples. The material calibration procedure revealed marked differences in the super-elastic properties of the materials employed in staple 1 and staple 2. The results obtained from the virtual bench testing framework have showed that both geometric features and material characteristics had a substantial impact on the mechanical properties of the device, especially on the generated force, whereas their effect on strain distribution and fatigue behavior was comparatively less pronounced. To conclude, this study advances the biomechanical understanding of Nitinol super-elastic staples by separately investigating the impact of geometry and material characteristics on the mechanical properties of two commercially available devices.

Influence of intracoronary hemodynamic forces on atherosclerotic plaque phenotypes.

BACKGROUND AND AIMS: Coronary hemodynamics impact coronary plaque progression and destabilization. The aim of the present study was to establish the association between focal vs. diffuse intracoronary pressure gradients and wall shear stress (WSS) patterns with atherosclerotic plaque composition. METHODS: Prospective, international, single-arm study of patients with chronic coronary syndromes and hemodynamic significant lesions (fractional flow reserve [FFR] ≤ 0.80). Motorized FFR pullback pressure gradient (PPG), optical coherence tomography (OCT), and time-average WSS (TAWSS) and topological shear variation index (TSVI) derived from three-dimensional angiography were obtained. RESULTS: One hundred five vessels (median FFR 0.70 [Interquartile range (IQR) 0.56-0.77]) had combined PPG and WSS analyses. TSVI was correlated with PPG (r = 0.47, [95% Confidence Interval (95% CI) 0.30-0.65], p < 0.001). Vessels with a focal CAD (PPG above the median value of 0.67) had significantly higher TAWSS (14.8 [IQR 8.6-24.3] vs. 7.03 [4.8-11.7] Pa, p < 0.001) and TSVI (163.9 [117.6-249.2] vs. 76.8 [23.1-140.9] m-1, p < 0.001). In the 51 vessels with baseline OCT, TSVI was associated with plaque rupture (OR 1.01 [1.00-1.02], p = 0.024), PPG with the extension of lipids (OR 7.78 [6.19-9.77], p = 0.003), with the presence of thin-cap fibroatheroma (OR 2.85 [1.11-7.83], p = 0.024) and plaque rupture (OR 4.94 [1.82 to 13.47], p = 0.002). CONCLUSIONS: Focal and diffuse coronary artery disease, defined using coronary physiology, are associated with differential WSS profiles. Pullback pressure gradients and WSS profiles are associated with atherosclerotic plaque phenotypes. Focal disease (as identified by high PPG) and high TSVI are associated with high-risk plaque features. CLINICAL TRIAL REGISTRATION: https://clinicaltrials,gov/ct2/show/NCT03782688.

Serial RV wall stress measurements: association with right ventricular function in repaired Tetralogy of Fallot patients.

Background: Optimal timing of pulmonary valve replacement (PVR) in Tetralogy of Fallot (TOF) patients remains challenging. Ventricular wall stress is considered to be an early marker of right ventricular (RV) dysfunction. Objectives: To investigate the association of RV wall stresses and their change over time with functional parameters in TOF patients. Methods: Ten TOF patients after surgical repair with moderate/severe pulmonary regurgitation were included. At two timepoints (median follow-up time 7.2 years), patient-specific computational biventricular models for wall stress assessment were created using CMR short-axis cine images and echocardiography-based RV pressures. RV ejection fraction (RVEF), NT-proBNP and cardiopulmonary exercise tests were used as outcome measures reflecting RV function. Associations between regional RV diastolic wall stress and RV function were investigated using linear mixed models. Results: Increased wall stress correlated with lower RV mass (rrm = -0.70, p = 0.017) and lower RV mass-to-volume (rrm = -0.80, p = 0.003) using repeated measures. Wall stress decreased significantly over time, especially in patients with a stable RVEF (p < 0.001). Higher wall stress was independently associated with lower RVEF, adjusted for left ventricular ejection fraction, RV end-diastolic volume and time since initial surgery (decrease of 1.27% RVEF per kPa increase in wall stress, p = 0.029) using repeated measurements. No association was found between wall stress, NT-proBNP, and exercise capacity. Conclusions: Using a computational method to calculate wall stress locally in geometrically complex ventricles, we demonstrated that lower wall stress might be important to maintain ventricular function. RV wall stress assessment can be used in serial follow-up, and is potentially an early marker of impending RV dysfunction.

Artificial Intelligence, Computational Simulations, and Extended Reality in Cardiovascular Interventions.

Artificial intelligence, computational simulations, and extended reality, among other 21st century computational technologies, are changing the health care system. To collectively highlight the most recent advances and benefits of artificial intelligence, computational simulations, and extended reality in cardiovascular therapies, we coined the abbreviation AISER. The review particularly focuses on the following applications of AISER: 1) preprocedural planning and clinical decision making; 2) virtual clinical trials, and cardiovascular device research, development, and regulatory approval; and 3) education and training of interventional health care professionals and medical technology innovators. We also discuss the obstacles and constraints associated with the application of AISER technologies, as well as the proposed solutions. Interventional health care professionals, computer scientists, biomedical engineers, experts in bioinformatics and visualization, the device industry, ethics committees, and regulatory agencies are expected to streamline the use of AISER technologies in cardiovascular interventions and medicine in general.

Impact of Post-PCI FFR Stratified by Coronary Artery.

BACKGROUND: Low fractional flow reserve (FFR) after percutaneous coronary intervention (PCI) has been associated with adverse clinical outcomes. Hitherto, this assessment has been independent of the epicardial vessel interrogated. OBJECTIVES: This study sought to assess the predictive capacity of post-PCI FFR for target vessel failure (TVF) stratified by coronary artery. METHODS: We performed a systematic review and individual patient-level data meta-analysis of randomized clinical trials and observational studies with protocol-recommended post-PCI FFR assessment. The difference in post-PCI FFR between left anterior descending (LAD) and non-LAD arteries was assessed using a random-effect models meta-analysis of mean differences. TVF was defined as a composite of cardiac death, target vessel myocardial infarction, and clinically driven target vessel revascularization. RESULTS: Overall, 3,336 vessels (n = 2,760 patients) with post-PCI FFR measurements were included in 9 studies. The weighted mean post-PCI FFR was 0.89 (95% CI: 0.87-0.90) and differed significantly between coronary vessels (LAD = 0.86; 95% CI: 0.85 to 0.88 vs non-LAD = 0.93; 95% CI: 0.91-0.94; P < 0.001). Post-PCI FFR was an independent predictor of TVF, with its risk increasing by 52% for every reduction of 0.10 FFR units, and this was mainly driven by TVR. The predictive capacity for TVF was poor for LAD arteries (AUC: 0.52; 95% CI: 0.47-0.58) and moderate for non-LAD arteries (AUC: 0.66; 95% CI: 0.59-0.73; LAD vs non-LAD arteries, P = 0.005). CONCLUSIONS: The LAD is associated with a lower post-PCI FFR than non-LAD arteries, emphasizing the importance of interpreting post-PCI FFR on a vessel-specific basis. Although a higher post-PCI FFR was associated with improved prognosis, its predictive capacity for events differs between the LAD and non-LAD arteries, being poor in the LAD and moderate in the non-LAD vessels.

Modelling blood flow in coronary arteries: Newtonian or shear-thinning non-Newtonian rheology?

BACKGROUND: The combination of medical imaging and computational hemodynamics is a promising technology to diagnose/prognose coronary artery disease (CAD). However, the clinical translation of in silico hemodynamic models is still hampered by assumptions/idealizations that must be introduced in model-based strategies and that necessarily imply uncertainty. This study aims to provide a definite answer to the open question of how to properly model blood rheological properties in computational fluid dynamics (CFD) simulations of coronary hemodynamics. METHODS: The geometry of the right coronary artery (RCA) of 144 hemodynamically stable patients with different stenosis degree were reconstructed from angiography. On them, unsteady-state CFD simulations were carried out. On each reconstructed RCA two different simulation strategies were applied to account for blood rheological properties, implementing (i) a Newtonian (N) and (ii) a shear-thinning non-Newtonian (non-N) rheological model. Their impact was evaluated in terms of wall shear stress (WSS magnitude, multidirectionality, topological skeleton) and helical flow (strength, topology) profiles. Additionally, luminal surface areas (SAs) exposed to shear disturbances were identified and the co-localization of paired N and non-N SAs was quantified in terms of similarity index (SI). RESULTS: The comparison between paired N vs. shear-thinning non-N simulations revealed remarkably similar profiles of WSS-based and helicity-based quantities, independent of the adopted blood rheology model and of the degree of stenosis of the vessel. Statistically, for each paired N and non-N hemodynamic quantity emerged negligible bias from Bland-Altman plots, and strong positive linear correlation (r > 0.94 for almost all the WSS-based quantities, r > 0.99 for helicity-based quantities). Moreover, a remarkable co-localization of N vs. non-N luminal SAs exposed to disturbed shear clearly emerged (SI distribution 0.95 [0.93, 0.97]). Helical flow topology resulted to be unaffected by blood rheological properties. CONCLUSIONS: This study, performed on 288 angio-based CFD simulations on 144 RCA models presenting with different degrees of stenosis, suggests that the assumptions on blood rheology have negligible impact both on WSS and helical flow profiles associated with CAD, thus definitively answering to the question "is Newtonian assumption for blood rheology adequate in coronary hemodynamics simulations?".

An agent-based model of cardiac allograft vasculopathy: toward a better understanding of chronic rejection dynamics.

Cardiac allograft vasculopathy (CAV) is a coronary artery disease affecting 50% of heart transplant (HTx) recipients, and it is the major cause of graft loss. CAV is driven by the interplay of immunological and non-immunological factors, setting off a cascade of events promoting endothelial damage and vascular dysfunction. The etiology and evolution of tissue pathology are largely unknown, making disease management challenging. So far, in vivo models, mostly mouse-based, have been widely used to study CAV, but they are resource-consuming, pose many ethical issues, and allow limited investigation of time points and important biomechanical measurements. Recently, agent-based models (ABMs) proved to be valid computational tools for deciphering mechanobiological mechanisms driving vascular adaptation processes at the cell/tissue level, augmenting cost-effective in vivo lab-based experiments, at the same time guaranteeing richness in observation time points and low consumption of resources. We hypothesize that integrating ABMs with lab-based experiments can aid in vivo research by overcoming those limitations. Accordingly, this work proposes a bidimensional ABM of CAV in a mouse coronary artery cross-section, simulating the arterial wall response to two distinct stimuli: inflammation and hemodynamic disturbances, the latter considered in terms of low wall shear stress (WSS). These stimuli trigger i) inflammatory cell activation and ii) exacerbated vascular cell activities. Moreover, an extensive analysis was performed to investigate the ABM sensitivity to the driving parameters and inputs and gain insights into the ABM working mechanisms. The ABM was able to effectively replicate a 4-week CAV initiation and progression, characterized by lumen area decrease due to progressive intimal thickening in regions exposed to high inflammation and low WSS. Moreover, the parameter and input sensitivity analysis highlighted that the inflammatory-related events rather than the WSS predominantly drive CAV, corroborating the inflammatory nature of the vasculopathy. The proof-of-concept model proposed herein demonstrated its potential in deepening the pathology knowledge and supporting the in vivo analysis of CAV.

Computational fluid dynamics as supporting technology for coronary artery disease diagnosis and treatment: an international survey.

Background: Computational fluid dynamics (CFD) is emerging as an effective technology able to improve procedural outcomes and enhance clinical decision-making in patients with coronary artery disease (CAD). The present study aims to assess the state of knowledge, use and clinical acceptability of CFD in the diagnosis and treatment of CAD. Methods: We realized a 20-questions international, anonymous, cross-sectional survey to cardiologists to test their knowledge and confidence on CFD as a technology applied to patients suffering from CAD. Responses were recorded between May 18, 2022, and June 12, 2022. Results: A total of 466 interventional cardiologists (mean age 48.4 ± 8.3 years, males 362), from 42 different countries completed the survey, for a response rate of 45.9%. Of these, 66.6% declared to be familiar with the term CFD, especially for optimization of existing interventional techniques (16.1%) and assessment of hemodynamic quantities related with CAD (13.7%). About 30% of respondents correctly answered to the questions exploring their knowledge on the pathophysiological role of some CFD-derived quantities such as wall shear stress and helical flow in coronary arteries. Among respondents, 85.9% would consider patient-specific CFD-based analysis in daily interventional practice while 94.2% declared to be interested in receiving a brief foundation course on the basic CFD principles. Finally, 87.7% of respondents declared to be interested in a cath-lab software able to conduct affordable CFD-based analyses at the point-of-care. Conclusions: Interventional cardiologists reported to be profoundly interested in adopting CFD simulations as a technology supporting decision making in the treatment of CAD in daily practice.

Multi-objective design optimization of bioresorbable braided stents.

BACKGROUND AND OBJECTIVES: Bioresorbable braided stents, typically made of bioresorbable polymers such as poly-l-lactide (PLLA), have great potential in the treatment of critical limb ischemia, particularly in cases of long-segment occlusions and lesions with high angulation. However, the successful adoption of these devices is limited by their low radial stiffness and reduced elastic modulus of bioresorbable polymers. This study proposes a computational optimization procedure to enhance the mechanical performance of bioresorbable braided stents and consequently improve the treatment of critical limb ischemia. METHODS: Finite element analyses were performed to replicate the radial crimping test and investigate the implantation procedure of PLLA braided stents. The stent geometry was characterized by four design parameters: number of wires, wire diameter, initial stent diameter, and braiding angle. Manufacturing constraints were considered to establish the design space. The mechanical performance of the stent was evaluated by defining the radial force, foreshortening, and peak maximum principal stress of the stent as objectives and constraint functions in the optimization problem. An approximate relationship between the objectives, constraint, and the design parameters was defined using design of experiment coupled with surrogate modelling. Surrogate models were then interrogated within the design space, and a multi-objective design optimization was conducted. RESULTS: The simulation of radial crimping was successfully validated against experimental data. The radial force was found to be primarily influenced by the number of wires, wire diameter, and braiding angle, with the wire diameter having the most significant impact. Foreshortening was predominantly affected by the braiding angle. The peak maximum principal stress exhibited contrasting behaviour compared to the radial force for all parameters, with the exception of the number of wires. Among the Pareto-optimal design candidates, feasible peak maximum principal stress values were observed, with the braiding angle identified as the differentiating factor among these candidates. CONCLUSIONS: The exploration of the design space enabled both the understanding of the impact of design parameters on the mechanical performance of bioresorbable braided stents and the successful identification of optimal design candidates. The optimization framework contributes to the advancement of innovative bioresorbable braided stents for the effective treatment of critical limb ischemia.

Investigating the effect of drug release on in-stent restenosis: A hybrid continuum - agent-based modelling approach.

BACKGROUND AND OBJECTIVE: In-stent restenosis (ISR) following percutaneous coronary intervention with drug-eluting stent (DES) implantation remains an unresolved issue, with ISR rates up to 10%. The use of antiproliferative drugs on DESs has significantly reduced ISR. However, a complete knowledge of the mechanobiological processes underlying ISR is still lacking. Multiscale agent-based modelling frameworks, integrating continuum- and agent-based approaches, have recently emerged as promising tools to decipher the mechanobiological events driving ISR at different spatiotemporal scales. However, the integration of sophisticated drug models with an agent-based model (ABM) of ISR has been under-investigated. The aim of the present study was to develop a novel multiscale agent-based modelling framework of ISR following DES implantation. METHODS: The framework consisted of two bi-directionally coupled modules, namely (i) a drug transport module, simulating drug transport through a continuum-based approach, and (ii) a tissue remodelling module, simulating cellular dynamics through an ABM. Receptor saturation (RS), defined as the fraction of target receptors saturated with drug, is used to mediate cellular activities in the ABM, since RS is widely regarded as a measure of drug efficacy. Three studies were performed to investigate different scenarios in terms of drug mass (DM), drug release profiles (RP), coupling schemes and idealized vs. patient-specific artery geometries. RESULTS: The studies demonstrated the versatility of the framework and enabled exploration of the sensitivity to different settings, coupling modalities and geometries. As expected, changes in the DM, RP and coupling schemes illustrated a variation in RS over time, in turn affecting the ABM response. For example, combined small DM - fast RP led to similar ISR degrees as high DM - moderate RP (lumen area reduction of ∼13/17% vs. ∼30% without drug). The use of a patient-specific geometry with non-equally distributed struts resulted in a heterogeneous RS map, but did not remarkably impact the ABM response. CONCLUSION: The application to a patient-specific geometry highlights the potential of the framework to address complex realistic scenarios and lays the foundations for future research, including calibration and validation on patient datasets and the investigation of the effects of different plaque composition on the arterial response to DES.

Aortic Remodeling Kinetics in Response to Coarctation-Induced Mechanical Perturbations.

Background: Coarctation of the aorta (CoA; constriction of the proximal descending thoracic aorta) is among the most common congenital cardiovascular defects. Coarctation-induced mechanical perturbations trigger a cycle of mechano-transduction events leading to irreversible precursors of hypertension including arterial thickening, stiffening, and vasoactive dysfunction in proximal conduit arteries. This study sought to identify kinetics of the stress-mediated compensatory response leading to these alterations using a preclinical rabbit model of CoA. Methods: A prior growth and remodeling (G&R) framework was reformulated and fit to empirical measurements from CoA rabbits classified into one control and nine CoA groups of various severities and durations (n = 63, 5-11/group). Empirical measurements included Doppler ultrasound imaging, uniaxial extension testing, catheter-based blood pressure, and wire myography, yielding the time evolution of arterial thickening, stiffening, and vasoactive dysfunction required to fit G&R constitutive parameters. Results: Excellent agreement was observed between model predictions and observed patterns of arterial thickening, stiffening, and dysfunction among all CoA groups. For example, predicted vascular impairment was not significantly different from empirical observations via wire myography (p-value > 0.13). Specifically, 48% and 45% impairment was observed in smooth muscle contraction and endothelial-dependent relaxation, respectively, which were accurately predicted using the G&R model. Conclusions: The resulting G&R model, for the first time, allows for prediction of hypertension precursors at neonatal ages that is currently challenging to examine in preclinical models. These findings provide a validated computational tool for prediction of persistent arterial dysfunction and identification of revised severity-duration thresholds that may ultimately avoid hypertension from CoA.

Is spontaneous coronary artery dissection (SCAD) related to local anatomy and hemodynamics? An exploratory study.

AIMS: Spontaneous coronary artery dissection (SCAD) is an increasingly diagnosed cause of myocardial infarction with unclear pathophysiology. The aim of the study was to test if vascular segments site of SCAD present distinctive local anatomy and hemodynamic profiles. METHODS: Coronary arteries with spontaneously healed SCAD (confirmed by follow-up angiography) underwent three-dimensional reconstruction, morphometric analysis with definition of vessel local curvature and torsion, and computational fluid dynamics (CFD) simulations with derivation of time-averaged wall shear stress (TAWSS) and topological shear variation index (TSVI). The (reconstructed) healed proximal SCAD segment was visually inspected for co-localization with curvature, torsion, and CFD-derived quantities hot spots. RESULTS: Thirteen vessels with healed SCAD underwent the morpho-functional analysis. Median time between baseline and follow-up coronary angiograms was 57 (interquartile range [IQR] 45-95) days. In seven cases (53.8%), SCAD was classified as type 2b and occurred in the left anterior descending artery or near a bifurcation. In all cases (100%), at least one hot spot co-localized within the healed proximal SCAD segment, in 9 cases (69.2%) ≥ 3 hot spots were identified. Healed SCAD in proximity of a coronary bifurcation presented lower TAWSS peak values (6.65 [IQR 6.20-13.20] vs. 3.81 [2.53-5.17] Pa, p = 0.008) and hosted less frequently TSVI hot spots (100% vs. 57.1%, p = 0.034). CONCLUSION: Vascular segments of healed SCAD were characterized by high curvature/torsion and WSS profiles reflecting increased local flow disturbances. Hence, a pathophysiological role of the interaction between vessel anatomy and shear forces in SCAD is hypothesized.